Glaucoma is second leading cause of irreversible blindness in the world affecting approximately 60 million people. Mutations in the gene encoding myocilin (MYOC) are responsible for most cases of juvenile onset glaucoma and 3-4% of adult onset primary open angle glaucoma. A number of laboratories have presented data demonstrating that mutations in MYOC result in retention of the protein in the endoplasmin reticulum (ER) and induction of ER stress responses. Using a novel transgenic mouse model we present functional data in this application to demonstrate that ER stress and subsequent activation of the Unfolded Protein Response (UPR) is a crucial step in the pathophysiology that leads to elevated IOP in myocilin-associated glaucoma. We further demonstrate that induction of UPR is sufficient to elicit IOP elevation in the absence of myocilin mutations. UPR is a general response to ER stress and can result from a variety of stressors, including mutations in other genes and environmental challenges. The proposed studies are based upon the hypothesis that mutations that result in protein misfolding in TM cells evoke chronic UPR, causing TM dysfunction and cell death, and ultimately result in IOP elevation. Therefore UPR may represent a general mechanism for elevation of IOP in POAG. The objective of this application is to determine whether UPR is a common mechanism leading to elevated IOP, not only in myocilin-associated glaucoma, but also in other types of primary open angle glaucoma. The proposed studies will be conducted using the exceptional resources available at the University of Iowa Glaucoma Center including the unique mouse model, our collection of several hundred well defined human donor eyes with and without glaucoma, excellent clinical resources, and expertise in the creation of human induced pluripotent stem cells. Confirmation of our hypothesis will not only identify the first cellular mechanism for the development of pathologically elevated IOP, but may also lead to novel medical approaches that could benefit millions of patients afflicted with POAG. PUBLIC HEALTH RELEVANCE: Glaucoma is a disease that causes vision loss and blindness in at least 3 million Americans and is associated with elevation of the intraocular pressure in the majority of glaucoma cases in North America and Europe. We have identified the first cellular mechanism that causes elevated pressure in a subset of patients. The proposed studies are designed to role of this mechanism in the overall glaucoma population. These data would significantly increase our understanding of the pathophysiology of the disease and provide novel targets for medical management of elevated intraocular pressure.